LRRK2 Kinase Inhibitor Rejuvenates Oxidative Stress-Induced Cellular Senescence in Neuronal Cells

Background. Leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the pathogenesis of Parkinson's disease (PD). Aging is the most critical risk factor for the progression of PD. The correlation between aging and cellular senescence has been established. Cellular senescence is correlated with the dysregulation of the proteolytic pathway and mitochondrial dysfunction, which are also associated with the aggregation of alpha-synuclein (alpha-syn). Methods. Human dopaminergic neuron-like cells (differentiated SH-SY5Y cells) were treated with rotenone in the presence or absence of the LRRK2 kinase inhibitor GSK2578215A (GSK-KI) for 48 h. The markers of cellular senescence, including p53, p21(Waf1/Cip1) (p21), beta-galactosidase (beta-gal), Rb phosphorylation, senescence-associated (SA) beta-gal activity, and lysosomal activity, were examined. The dSH cells and rat primary cortical neurons were treated with alpha-syn fibrils 30 min before treatment with rotenone in the presence or absence of GSK-KI for 48 h. Mice were intraperitoneally injected with rotenone and MLi-2 (LRRK2 kinase inhibitor) once every two days for two weeks. Results. Rotenone upregulated LRRK2 phosphorylation and beta-gal levels through the activation of the p53-p21 signaling axis and downregulated Rb phosphorylation. Additionally, rotenone upregulated SA beta-gal activity, reactive oxygen species levels, and LRRK2 phosphorylation and inhibited lysosome activity. Rotenone-induced LRRK2 upregulation impaired the clearance of alpha-syn fibrils. Treatment with LRRK2 inhibitor mitigated rotenone-induced cellular senescence and alpha-syn accumulation. Conclusions. Rotenone-induced upregulation of LRRK2 kinase activity promoted cellular senescence, which enhanced alpha-syn accumulation. However, the administration of an LRRK2 kinase inhibitor rejuvenated rotenone-induced cellular senescence.

Automated summary

The study revealed that rotenone-induced upregulation of LRRK2 kinase activity promoted cellular senescence, leading to increased accumulation of alpha-synuclein. Treatment with an LRRK2 kinase inhibitor mitigated cellular senescence and alpha-synuclein accumulation induced by rotenone.